EP1171105B1 - Transdermal therapeutic system with a highly effective neuroleptic agent - Google Patents

Description

Fluphenazine is a tricyclic, very potent neuroleptic from the group of perphenazines. These substances have an antipsychotic effect, especially in schizophrenic psychoses, without significantly affecting consciousness and intellectual ability. The typical oral daily dose is 3-6 mg, under steady-state conditions up to 24 mg (see Mutschler E. "Arzneimittelwirkungen", 6th ed., Wissenschaftliche Verlagsgesellschaft Stuttgart 1991).
The half-life in the blood plasma is 15 h. For intravenous therapy are the ester forms, such as decanoate and
Enanthate, each with a significantly extended half-life available. In oral therapy, the dihydrochloride of fluphenazine is used (see Red List Win 1997 / II Verse 2.4, RED LIST Service GmbH, ECV Editio Cantor Verlag).

Therapy to treat schizophrenic psychoses of patients typically requires chronic, often lifelong administration of appropriate drugs.
Patients are often only conditionally or only occasionally responsive, so that an active participation in the therapy is often not achievable. An independent intake by the patient is therefore associated with great uncertainties.

It is therefore an object of the invention to provide a fluphenazine-containing transdermal therapeutic system (TTS), which delivers at least 1 ug / cm ² · d drug to the human skin and thus the once or even repeated daily oral intake by a 1-3 times weekly Application replaced.

The problem can be solved by the TTS one Enhancer has and a skin-side pressure-sensitive adhesive layer based on polymers that own pure hydrocarbon represent.

The development of corresponding transdermal therapeutic systems was previously the presumption of a very low skin permeability for fluphenazine and especially its salts.
For fluphenazine dihydrochloride, a poor permeability in human skin is therefore to be expected because of the salt structure and the associated hydrophilicity. To make matters worse, the relatively high molecular weight of 437.53 Da and the sterically fixed tricyclic in the molecule are added.

The transdermal intake of several milligrams per day, on an acceptable application area of max. 50 cm ² , therefore encounters certain reservations.
Consequently, there are no descriptions in the literature for practical transdermal systems that achieve systemic efficacy.
On the contrary, fluphenazine is only mentioned in the patent literature at those points where TTS with certain physicochemical properties (US Pat. No. 5,474,783) or additives are described (US Pat. No. 5,120,545), without making any reference to concrete examples of this active substance. These patents include fluphenazine merely as a potential drug from a purely theoretical list of conceivable drugs.

For example, EP 0 452 837 discloses a transdermal Therapeutic system in plaster form, which consists of a Active ingredient, a hydrophobic polymer with a glass transition temperature from -65 ° C to 35 ° C, a percutaneous absorption enhancer and a hydrophilic polymer, the is water-soluble or swellable in water. When Active ingredient is fluphenazine HCl in addition to many other active ingredients or flupentixol, as a hydrophobic polymer Polyisobutylenes should also be considered, too when (meth) acrylate copolymers with functional monomers particularly preferred. US 5,882,676 discloses transdermal therapeutic systems in which the permeation enhancer Acyllactylate as an essential ingredient besides the active ingredient, u. a. Fluphenazine or triflupromazine, in a matrix, u. a. embedded on a polyisobutin basis is. However, neither EP 0 452 837 nor US 5,882,676 discloses concrete examples of transdermal therapeutic systems, containing the active ingredients claimed herein.

Recent studies on the pharmacokinetics of fluphenazine following oral administration have recently been published (Koytchev R et al .: "Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers", Eur. J. Clin. Pharmacol., 1996; 51: 183-187 ). As a result, only about 2.5 to 3.5% of the orally administered dose of fluphenazine in the blood becomes available.
The direct administration into the bloodstream bypassing the digestive tract and first-pass effect in the liver, as it is possible transdermally, would therefore be possible with a fraction of the typical oral dose.

A typical transdermal daily dose should be 90 to 180 μg, under steady-state conditions up to 840 μg be.

All studies were performed with fluphenazine dihydrochloride (ICN Biomedicals Inc. Ohio, USA). This substance form is used worldwide therapeutically, so that in contrast to the free base on very extensive toxicological and regulatory dossiers can be accessed. Examination of skin permeability was carried out in vitro using cow uterine skin or human epidermis separated by heat separation of human whole skin.
The experiments were carried out at 32 ° C in a suitable permeation apparatus (modified Franz cell) and measured in the samples obtained fluphenazine by a suitable HPLC method. All values are based on n = 3 samples.

As part of the matrix or drug-in-adhesive technology, pressure-sensitive adhesive films based on poly (meth) acrylates as matrices were first investigated. These were the market products Durotak 387-2051, Durotak 387-2287 and Durotak 387-2353 (National Starch and Chemical Co.).
Such pressure-sensitive adhesives are widely used in medical products because of their ease of construction and their low allergenic potential.

The dihydrochloride salt is almost insoluble in such polymers or the organic solvents required for processing. It was therefore provided in all cases an addition of Eudragit E100 (Röhm Pharma GmbH). This poly (meth) acrylate copolymer of neutral methacrylic acid esters and dimethylaminoethyl methacrylate has trialkylamino groups in the side chain and is capable of functioning as an anion exchange resin. In this sense, the chloride ions of the fluphenazine dihydrochloride are bound to Eudragit E100 with simultaneous uptake of protons, whereby fluphenazine is formed as a free base in a certain equilibrium.
Convenient is an at least equimolar ratio of Eudragit E100 and fluphenazine dihydrochloride, ie, amounts by weight that have the same equivalent weight calculated as potassium hydroxide. The amount of the alkaline additive, preferably a polymer such as. B. Eudragit E100, but may also preferably 0.5 to 1.5 times equivalent weight of the amount of active ingredient contained, expressed as potassium hydroxide correspond.

In this procedure, a surprisingly high solubility of at least 15 wt.% Fluphenazine dihydrochloride in Durotak 387-2051 was found, for Durotak 387-2287 still at least 10 wt.%.
Nevertheless, the permeation rates of ileal udder skin were very low (examples Flu1-Flu5, see FIG.1, see Table 1).
The carboxyl group-free Durotak 387-2287 (see Example Flu5), however, proved to be clearly superior to the carboxyl-containing 387-2051 (see Examples Flu3 and Flu5). Carboxyl groups are apparently hindered by the ability to salt with fluphenazine base for its release. This assumption could be confirmed by neutralizing Durotak 387-2051 with an equimolar amount of potassium hydroxide under otherwise identical conditions (see Examples Flu2 and Flu4). This resulted in increased premeation values, which nevertheless did not match the neutral Durotak 387-2287.
Overall, adhesive matrices based on poly (meth) acrylate have a high solubility of fluphenazine with simultaneously poor release.
Thus, in particular the quantitative utilization of the active substance contained is very bad.
Surprisingly, this could be improved by additives. Both the fatty alcohol 2-octyl-dodecanol (Eutanol® G) and the fatty acid oleic acid markedly increased the permeation through the iliac skin (see Fig. 2, see Table 2).
In particular, the fatty acid shows clearly positive effects that can be based on ion pair formation with fluphenazine base. The good skin permeability of such ion-pair complexes is known in the art.

So while the use of a basic adjuvant like Eudragit E100 with simultaneous use of an acidic Excipients such as oleic acid provides significant benefits As a result, poly (meth) acrylate-based pressure-sensitive adhesives appear as little suitable matrix.

The developed principle was therefore transferred to other possible adhesive matrices.
Surprisingly, it has been found here that a polymer matrix based on pure hydrocarbons (Oppanol B10 and B100) leads to very greatly improved permeation rates through ileal uterine skin (see FIG.3, see Table 3).

Especially in the early stages of the experiment, after 24 and 32 hours, there is a considerable advantage over comparable matrices.
The pressure-sensitive adhesive formulation based on pure hydrocarbon polymers thus shows clear advantages over poly (meth) acrylates and surprisingly also over a silicone adhesive (BioPSA Q7-4301, Dow Corning Chem.Co.).

Preferably, the skin-side pressure-sensitive adhesive layer is in essentially from polymers from the group of polyisobutylenes or the polyisoprenes. According to a particular embodiment is provided that this layer of two to three different Polymers is built up that have the same molecular structure differ only in their mean molecular weights.

Especially the ratio of drug loading (now only 5 wt .-%, preferably between 0.5 and 5 wt .-% active ingredient in the matrix layer) to drug permeation and thus the degree of utilization have improved significantly.

In another experiment, the optimized formula was finally tested on human epidermis. The data obtained give an excellent permeation curve with short Lagtime and approximately linear characteristic (see FIG.4).
An equimolar ratio of fluphenazine, Eudragit E100 and oleic acid (based on the respective equivalent weights, calculated as potassium hydroxide) proved to be optimal. Both an increase in the proportion of oleic acid and the Eudragit E100 led in each case to worse results (see FIG.4, see Table 4).

Maximum flow rates of 2.9 μg / h.cm ² fluphenazine base were achieved.
The expected transdermal daily dose of 90-180 μg fluphenazine (see above) could thus be achieved with only about 2-4 cm ² TTS. Even the 840 micrograms daily that may be required during inpatient therapy could be achieved transdermally with a system less than 20 cm ^{2 in} size.

Based on these data, transdermal therapy with Fluphenazine has become possible. It is within the scope of the invention even surprisingly small TTS possible.

The invention makes it possible to carry out the transdermal therapy with fluphenazine at a dosage which is far below the orally required amounts.
Transdermal therapy with fluphenazine is not only an alternative route of administration, but also offers advantages over conventional long-term oral therapy because of its greater dose-related efficacy.

Because of the great chemical similarity, the similar pharmacodynamic effect, the comparable required therapeutic dosages and the expected similarity of the pharmacokinetics, the invention can be applied to the following further active substances:

For flupentixol, the cis isomer (α-flupentixol) is due to to favor its greater pharmacodynamic potency.

The active substance may also be a pharmaceutical acceptable salt form, preferably around the hydrochloride or dihydrochloride.

In particular, the invention therefore extends to transdermal therapeutic systems consisting of a backing layer, at least one active ingredient-containing matrix layer, which may also have pressure-sensitive adhesive properties, and a removable protective layer, wherein with these systems, a release rate of at least 1 ug / cm ² · d of a Neuroleptic, selected from the fluphenazine, flupentixol and triflupromazine group, to which human skin is reached.

The invention further relates to a method of administering to a subject a highly effective antipsychotic agent which requires treatment with such an agent wherein the agent is fluphenazine and delivered to the human skin at a rate of at least 1 μg / cm ² .d , In a corresponding manner and at the stated rate, the active substances flupentixol or triflupromazine can also be released into the human skin using such a method.

The transdermal therapeutic systems of the invention can thus be used to administer a highly effective neuroleptic, selected from the fluphenazine, flupentixol and Triflupromazine comprehensive group, to a person which the treatment needed with such an active ingredient is used become.

The inventive method for administering said Neuroleptics and the use of the invention TTSs for administration of these neuroleptics are especially beneficial in the treatment of patients who suffer from psychosis or schizophrenic psychosis. As mentioned at the beginning, is especially in such Patients who are usually treated with medication for a longer period of time must be, the oral administration of drugs associated with disadvantages.

In the following, attention is drawn to further requirements for a TTS:

Because of the known photoreactivity of the Phenothiazingerüstes stabilizing additives may be necessary. In addition to UV radiation absorbing substances or pigments, these are especially antioxidants. These are preferably ascorbyl palmitate, vitamin E and its pharmaceutically acceptable esters, as well as butylated hydroxyanisole (BHA) and butylhydroxytoluene (BHT). Sulfur-containing stabilizers such as methionine or inorganic sulfites may also be required. The use of hexamethylenetetramine (methenamine) as specific stabilizer for phenothiazines is possible (s. Monograph "phenothiazine" in The Merck Index, 12 ^th Edition, 1996).

The addition of such substances typically occurs in concentrations of less than 1% by weight, preferably in an amount of 0.01 to 1.0 wt .-%, to the active ingredient-containing matrix of the TTS.

In terms of photosensitivity may continue make sense, as the back layer of the TTS one by pigmentation, Paint or metallization opaque made film or a corresponding composite material to use.

Furthermore, it is provided according to a further embodiment, that a Tackifier is included in the TTS as an additive, preferably from the group of mineral oil as well as natural or synthetic resins.

The permeation enhancer mentioned may preferably be a saturated or monounsaturated fatty acid of the general formula H _{2x + 1} C _x -COOH or H _2x-1 C _x -COOH for X = S to 17, in particular undecylenic acid, lauric acid , Myristic acid or oleic acid, wherein the fatty acid is added in an amount corresponding preferably to 0.5 to 1.5 times equivalent weight of the amount of the active ingredient contained, calculated as potassium hydroxide.

Furthermore, the permeation enhancer may be a saturated or monounsaturated fatty alcohol of the general formula H _{2x + 1} C _x -CH ₂ -OH or H _2x-1 C _x -CH ₂ -OH for X = 5 to 17 , in particular 1-decanol, 1-dodecanol, oleyl alcohol or the branched-chain alcohol 2-octyl-dodecanol, this enhancer being contained in an amount of preferably 1 to 20 wt .-% in the active substance-containing matrix layer.

Further preferred compounds are permeation enhancers from the group of the fatty alcohol polyoethyl ethyl ether, the fatty acid methyl styrene, the Fottsäureothylester, the isopropyl acetate, the fatty acid lactates or fatty alcohol fatty acid esters into consideration, wherein the enhancer in each case in an amount of preferably 1 to 20 wt .-% in the active ingredient Matrix layer is included.

Examples 1 to 13:

The preparation of the example formulations Flul to Flu13 was carried out under the general conditions described below:
The various Durotak adhesives and the silicone adhesive were used in the form of solutions supplied by the manufacturer in organic solvents.
Eudragit E100 was processed in the form of a solution in ethyl acetate (60% by weight).
The mixture of 75 parts by weight of Oppanol B10 with 25 parts by weight of Oppanol B100 was used as a solution in special spirit 80-110 (31% by weight).
The neutralization of carboxyl-containing polyacrylate adhesive (Durotak 387-2051 and 387-2353) was carried out by reacting these Kleborlösungen with potassium hydroxide in methanolic solution (10 wt .-%). The amount of potassium hydroxide used corresponded to the lower limit of the manufacturer's specified potassium hydroxide number (mg KOH / g polymer) for the respective product.

The stated amount of fluphenazine dihydrochloride (fluphenazine · 2 HCl) was first mixed with the Eudragit solution before the pressure-sensitive adhesive solutions and, if appropriate, further constituents were incorporated. Any necessary dilution of the composition to a suitable viscosity was carried out with ethyl acetate.
The homogeneously stirred masses were coated with a bar applicator on a 100 micron thick film of siliconized polyethylene terephthalate (PET) and then dried for 5 minutes at 80 ° C in an air oven.
The dried adhesive film was covered with a PET film (15 μm thick) as a protective film.
The basis weight of the adhesive matrix was adjusted to 80 g / m ² in all cases by suitably selecting the coating thickness.

The compositions of the example formulations reproduced here in tabular form relate to the dried active substance-containing layer of the TTS (Tab.1 to 4). Composition of the pressure-sensitive adhesive matrix layer in percent by weight: ingredients Example Flu1 Example Flu2 Example Flu3 Example Flu4 Example Flu5 Fluphenazine 2 HCl 11.7 11.7 17.6 17.6 11.7 Eudragit E100 14.3 14.3 21.5 21.5 14.3 Durotak 387-2051 74.0 --- 39.1 --- --- Durotak 387-2051 potassium salt * --- 74.0 --- 39.1 --- Durotak 387-2287 --- --- --- --- 74.0 Total 100.0 100.0 100.0 100.0 100.0 Composition of the pressure-sensitive adhesive matrix layer in percent by weight: ingredients Example Flu6 Example Flu7 Fluphenazine 2 HCl 11.7 11.7 Eudragit E100 14.3 14.3 oleic acid 6.5 --- Eutanol G --- 5.0 Durotak 387-2051 potassium salt * 67.5 69.0 Total 100.0 100.0 Composition of the pressure-sensitive adhesive matrix layer in percent by weight: ingredients Example Flu8 Example Flu9 Example Flu10 Example Flu11 Fluphenazine 2 HCl 5.83 5.83 5.83 5.83 Eudragit E100 7.15 7.15 7.15 7.15 oleic acid 3.22 3.22 3.22 3.22 Eutanol G --- --- 20.0 --- Organic PSA Q7-4301 83.8 --- --- --- Durotak 387-2287 --- 83.8 63.8 --- Durotak 387-2353 potassium salt * --- --- --- --- Oppanol B10 / B100 75 + 25 * --- --- --- 83.8 Total 100.0 100.0 100.0 100.0 Composition of the pressure-sensitive adhesive matrix layer in percent by weight: ingredients Example Flu12 Example Flu13 Fluphenazine 2 HCl 5.83 5.83 Eudragit E100 10.7 7.15 oleic acid 3.22 4.83 Oppanol B10 / B100 75 + 25 * 80.3 82.2 Total 100.0 100.0

Claims (15)

1. Transdermal therapeutic system consisting of a backing layer, at least one active substance-containing matrix layer, which may at the same time possess pressure-sensitive adhesive properties, as well as a removable protective layer, characterized by a content of a neuroleptic, a content of at least one permeation enhancer, as well as by a layer which is pressure-sensitive adhesive on the skin-facing side and based on polymers which are pure hydrocarbons.
2. Transdermal therapeutic system according to Claim 1, characterized in that the neuroleptic is fluphenazine, flupentixol or triflupromazine.
3. Transdermal therapeutic system according to Claim 1 or 2, characterized in that the active substance concentration in the matrix layer is between 0.5 and 5.0%-wt.
4. Transdermal therapeutic system according to one or more of Claims 1 to 3, characterized in that the release rate of the neuroleptic is at least 1 µg/cm²·d.
5. Transdermal therapeutic system according to one or more of Claims 1 to 4, characterized in that the active substance contained is a pharmaceutically acceptable salt form, preferably that of the hydrochloride or the dihydrochloride.
6. Transdermal therapeutic system according to one or more of the preceding Claims, characterized in that an alkaline-reacting additive is contained, preferably in an amount corresponding to 0.5 to 1.5 times the equivalent weight of the active substance amount contained, expressed as potassium hydroxide.
7. Transdermal therapeutic system according to one or more of the preceding claims characterized in that the alkaline additive is a polymer, preferably a copolymer of dimethylaminoethyl methacrylate and methacrylate units.
8. Transdermal therapeutic system according to Claim 1, characterized in that the permeation enhancer is a saturated or monounsaturated fatty acid of the general formula H_2x+1C_x-COOH and H_2x-C_x-COOH, respectively, for X = 5 to 17, especially undecylenic acid, lauric acid, myristic acid or oleic acid, in an amount of preferably 0.5 to 1.5 times the equivalent weight of the active substance amount contained, calculated as potassium hydroxide.
9. Transdermal therapeutic system according to Claim 1, characterized in that the permeation enhancer is a saturated or monounsaturated fatty alcohol of the general formula H_2x+1C_x-CH₂-OH and H_2x-1C_x-CH₂-OH, respectively, for X = 5 to 17, especially 1-decanol, 1-dodecanol, oleyl alcohol or the branched-chain alcohol 2-octyl dodecanol, in an amount of preferably 1 to 20%-wt. relative to the active substance-containing matrix layer.
10. Transdermal therapeutic system according to Claim 1, characterized in that the permeation enhancer is a compound from the group of fatty alcohol polyoxyethyl ethers, the fatty acid methyl esters, the fatty acid ethyl esters, the fatty acid isopropyl esters, the fatty acid lactates or the fatty alcohol fatty acid esters in an amount of preferably 1 to 20%-wt., relative to the active substance-containing matrix layer.
11. Transdermal therapeutic system according to Claim 1, characterized in that in that the layer which is pressure-sensitive adhesive on the skin-facing side substantially consists of polymers from the group of polyisobutylenes or polyisoprenes.
12. Transdermal therapeutic system according to Claims 1, and 10, characterized in that the layer which is pressure-sensitive adhesive on the skin-facing side is made up of two to three different polymers which having the same molecular structure differ only in their mean molecular weight.
13. Transdermal therapeutic system according to Claim 1, characterized in that as active substance a tackifier, preferably from the group of mineral oils as well as of natural or synthetic resins, is contained.
14. Transdermal therapeutic system according to one or more of the preceding Claims, characterized in that a stabilizing additive from the group of antioxidants or hexamethylenetetramine is contained in an amount of preferably 0.01 to 1.0%-wt. in the pressure-sensitive adhesive layer.
15. Transdermal therapeutic system with a content of a neuroleptic of the group comprising fluphenazine, flupentixol and triflupromazine, consisting of a backing layer, at least one active substance-containing matrix layer, which may at the same time possess pressure-sensitive adhesive properties, as well as a removable protective layer, characterized in that the matrix layer is a polymer layer based on pure hydrocarbons and contains at least one permeation enhancer, and that the said transdermal therapeutic system releases the neuroleptic to the human skin at a release rate of at least 1 µg/cm²·d.

Images